Neural Basis of Hyposmia in Alzheimer’s Disease

Abstract

At the beginning of twenty century Alois Alzheimer described the pathology that now bears his name (Alzheimer, 1907). Over a hundred years later, Alzheimer’s disease (AD) is the most common cause of dementia in developed countries. Here eighteen million people are currently affected and the number of patients is expected to increase dramatically with the ongoing increase in the elderly population (Fotuhi et al., 2009, Mount & Downton, 2006). Because no suitable biomarkers are available, the diagnosis of AD remains inconclusive until postmortem pathological analysis, and physicians rely on behavioral manifestations to differentiate between AD and other conditions. For this reason firm diagnosis is generally only made at later stages of the disorder when treatment is purely palliative. These features make AD a social and economic challenge in developed countries (Wimo et al., 2010). Clinically, AD is characterized by progressive loss of cognitive functions with specific deficits in episodic memory. Clinical diagnosis of is generally only made when cognitive deficits are sufficiently severe to cause dependent status of the patient (Nestor et al., 2004). Pathological analyses of AD brain have described two distinct types of proteinopathy in the frontal and temporal lobes involving the limbic system and the basal forebrain. The first type comprises aggregates of beta-amyloid peptide (Aβ) – a specific fragment of the amyloid precursor protein (APP), a plasma membrane protein. These aggregates accumulate in the extracellular space and give rise to senile plaques (SPs). SPs cause synaptotoxicity, neurotoxicity, oxidative stress and hypoxia (Peers et al., 2009, Selkoe, 2001, 2008). The second proteinopathy occurs in the cytosol. Hyperphosphorylation and abnormal aggregation of the microtubule-associated protein tau leads to the intracellular formation of neurofibrillary tangles (NFTs) which cause cytoskeleton destabilization and eventually cell death (Hernandez & Avila, 2008, Selkoe, 2001). It has been widely reported that olfactory loss (anosmia and hyposmia) takes place in the early stages of AD, and before any detectable cognitive deficits are present. Interestingly, AD pathology extends throughout the limbic system and the basal forebrain, including the olfactory system (Braak & Braak, 1991). The human olfactory system includes peripheral sensory neurons in the olfactory epithelium; these send their axons across the cribriform plate of the etmoides bone to the olfactory bulbs. In the glomerular layer of the olfactory